Development of Important Immune Cells
Relies on More Complicated Influences than Scientists
Had Thought

Research by Penn Cancer Center's Abramson Family Cancer
Research Institute Shows It Isn't all 'Nurture' in the
Nature Vs. Nurture Debate About How Cells Develop

Researchers
studying the way immune cells differentiate have discovered
that an important family of white blood cells divides
into separate identities in a much more complicated
fashion than current scientific theory has held.

Led by Steven L. Reiner, MD, of the Leonard & Madlyn
Abramson Family Cancer Research Institute at the University
of Pennsylvania Cancer Center, the researchers have
overturned existing scientific belief that helper T
cells are programmed to differentiate only by outside
signals.

Instead, the researchers have shown that Th1 and Th2
cells -- which are involved in inflammatory and allergic
responses, respectively -- develop in a delicate chronological
pattern, and in response to both internal and external
influences.

The finding, which will be published in the June 8 issue
of the journal Science, clears a new path for inquiry
in the development of drugs that can create reinforcements
for the body's army of immune cells.

"The cell isn't just a tabula rasa -- a blank slate
completely open to outside instructions. The cell is
actively making decisions on its own that are sometimes
hard for us to see," said Reiner, an Associate
Investigator for the Abramson Institute and an Associate
Professor in Penn's Department of Medicine.

Establishing how these white blood cells develop will
someday help scientists to manipulate their production,
increasing the supply of Th1 cells to fight against
some parasite-caused illnesses or intracellular bacterial
infections such as tuberculosis, or pumping up the supply
of Th2 cells to combat autoimmune diseases and extracellular
microbes such as intestinal worms.

In their work, Reiner and his colleagues scrutinized
the cascade of events that follow when uncommitted cells
are exposed to a protein factor called interleukin 12
(IL-12). It is well known that, when IL-12 is present,
Th1 cells predominate. Common scientific thinking has
held that this results because IL-12 'instructs' undecided
cells to become Th1 cells.

Reiner and his team challenged the prevailing opinion
in order to establish how
the process really operates. "That 'instructive'
model makes sense intuitively," Reiner said, "But
an alternative hypothesis -- which seemed to make more
sense the more we learned -- is that development from
uncommitted cells to Th1 cells takes place spontaneously,
almost imperceptibly, and that IL-12 performs a separate
function. Instead, it looks like IL-12 promotes the
growth of the cell once it has spontaneously altered."

That happens, Reiner says, because "part of adopting
the new fate of Th1 cells includes a special ability
to grow in response to the IL-12 protein.

"For many scientists, the therapeutic objective
is to change the fate of a cell," Reiner said.
"Now we know it isn't all 'nurture' in the 'nature
versus nurture' question. The cell has some say in the
decision, and understanding that brings us closer to
our goal."

Reiner was assisted in the study by Alan C. Mullen,
Frances A. High, Anne S. Hutchins, Hubert W. Lee and
Alejandro V. Villarino, all of the Abramson Institute;
David M. Livingston, PhD, and Andrew L. Kung, MD, PhD,
both of the Dana Farber Cancer Institute; Nezih Cereb,
MD, of Histogenetics, Inc. and the Center for Genetic
Polymorphism; Tso-Pang Yao, PhD, of Duke University,
and Soo Y. Yang, PhD, also of Histogenetics and the
Center for Genetic Polymorphism.